Abstract
Histamine H3 receptor antagonists are being developed to treat a variety of neurological and cognitive disorders that may be ameliorated by enhancement of central neurotransmitter release. Here, we present the in vitro pharmacological and in vivo pharmacokinetic profiles for the nonimidazole, benzofuran ligand ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] and compare it with several previously described imidazole and nonimidazole H3 receptor antagonists. ABT-239 binds to recombinant human and rat H3 receptors with high affinity, with pKi values of 9.4 and 8.9, respectively, and is over 1000-fold selective versus human H1, H2, and H4 histamine receptors. ABT-239 is a potent H3 receptor antagonist at recombinant human and rat receptors, reversing agonist-induced changes in cAMP formation (pKb = 7.9 and 7.6, respectively), guanosine 5′-O-(3-[35S]thio) triphosphate ([35S]GTPγS) binding (pKb = 9.0 and 8.3, respectively), and calcium mobilization (human pKb = 7.9). ABT-239 also competitively reversed histamine-mediated inhibition of [3H]histamine release from rat brain cortical synaptosomes (pKb = 7.7) and agonist-induced inhibition of contractile responses in electric field stimulated guinea pig ileal segments (pA2 = 8.7). Additionally, ABT-239 is a potent inverse agonist, inhibiting constitutive [35S]GTPγS binding at both rat and human H3 receptors with respective pEC50 values of 8.9 and 8.2. ABT-239 demonstrates good pharmacokinetic characteristics in rat, dog, and monkey with t1/2 values ranging from 4 to 29 h, corresponding with clearance values and metabolic turnover in liver microsomes from these species, and good oral bioavailability ranging from 52 to 89%. Thus, ABT-239 is a selective, nonimidazole H3 receptor antagonist/inverse agonist with similar high potency in both human and rat and favorable drug-like properties.
Footnotes
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This work was supported by Abbott Laboratories. Portions of this work were previously presented at the 32nd Annual European Histamine Research Society Meeting, Düsseldorf/Köln, Germany, May 7 to 11, 2003, and at the 33rd Annual Society for Neuroscience Meeting, New Orleans, LA, November 8 to 12, 2003.
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doi:10.1124/jpet.104.078303.
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ABBREVIATIONS: CNS, central nervous system; 5-HT, 5-hydroxytryptamine; P450, cytochrome P450; A-304121, 4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)(cyclopropyl)methanone; A-317920, N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl-)-2-furamide; A-349821, (4′-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone; ABT-239, 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile; GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate; [3H]LY-278584, 1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1H-indazole-3-carboxamide; (R)-α-MeHA, (R)-α-methylhistamine; HEK, human embryonic kidney; EFS, electric field stimulation; LC/MS, liquid chromatography/mass spectrometry.
- Received September 23, 2004.
- Accepted December 13, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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